Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive, lethal cancer characterized by extensive genomic instability and aneuploidy. One of the signature alterations of PDAC is inactivation of the p14ARF (Alternative Reading Frame) tumor suppressor. It has been shown that ARF-p53 signaling is disrupted in 50-75% of human cases and plays a critical role in restraining PDAC progression in genetically engineered mouse models of the disease. Importantly, ARF also functions independent of the p53 tumor suppressor to prevent cancer. As such, components of ARF's p53-independent signaling may be disrupted in the remaining 25-50% of PDAC that retain wild type ARF and p53. We recently discovered a novel Partner of ARF (Parf) that is required for ARF signaling in the absence of p53. Parf also acts independent of ARF to maintain genomic stability and restrain the proliferation of multiple cell types, particularly pancreatic cancer lines. The Parf transcript and protein is most highly expressed in the normal pancreas compared to other tissues and there is evidence for its inactivation in human PDAC. These findings support the hypothesis that Parf is a novel tumor suppressor gene that promotes genomic stability and inhibits the malignant progression of pancreatic cancer. Moreover, because Parf exhibits anticancer activities that intersect with ARF as well as other anticancer pathways, we speculate it could be targeted for inactivation in both ARF-positive and ARF-negative tumors. This proposal tests these ideas using molecular approaches and mouse models of PDAC. Aim 1 will determine if inactivation of Parf occurs in advanced stages of PDAC that exhibit increased chromosomal instability. Aim 2 uses novel mouse models to test if Parf normally suppresses PDAC development and/or metastasis in vivo. This work will advance our understanding of the molecular basis of PDAC and result in new experimental models for human pancreatic cancer, thereby facilitating improved detection and treatment of PDAC. These goals directly address key initiatives defined in the program announcement for Pilot Studies in Pancreatic Cancer. PUBLIC HEALTH RELEVANCE: Pancreatic ductal adenocarcinoma (PDAC) is arguably the deadliest of all cancers in the United States due to lack of early detection and ineffective treatments. This study will advance our understanding of the molecular basis of PDAC and provide new experimental models for human pancreatic cancer, thereby facilitating improved detection and treatment of this currently incurable and devastating disease.